Diabetes and obesity are increasing health problems globally and are associated with various other diseases, particularly cardiovascular diseases (CVD), obstructive sleep apnea, stroke, peripheral artery disease, microvascular complications and osteoarthritis. There are 246 million people worldwide with diabetes, and by 2025 it is estimated that 380 million will have diabetes. Many have additional cardiovascular risk factors including high/aberrant LDL and triglycerides and low HDL. Cardiovascular disease accounts for about 50% of the mortality in people with diabetes, and the morbidity and mortality rates relating to obesity and diabetes underscore the medical need for efficacious treatment options.
Pre-proglucagon is a 158 amino acid precursor polypeptide that is processed in different tissues to form a number of different proglucagon-derived peptides, including glucagon, glucagon-like peptide-1 (GLP-1 or GLP1), glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM), which are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake. Glucagon is a 29-amino acid peptide that corresponds to amino acids 33 through 61 of pre-proglucagon, while GLP-1 is produced as a 37-amino acid peptide that corresponds to amino acids 72 through 108 of pre-proglucagon.
When blood glucose begins to fall, glucagon, a hormone produced by the pancreas, signals the liver to break down glycogen and release glucose, causing blood glucose levels to rise toward a normal level. In addition to controlling glucose homeostasis, glucagon reduces body weight probably through inhibition of food intake and stimulation of energy expenditure and/or lipolysis. GLP-1 has different biological activities compared to glucagon. Its actions include stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, and inhibition of food intake. GLP-1 has been shown to reduce hyperglycemia (elevated glucose levels) in diabetic patients. Exendin-4, a peptide from lizard venom that shares about 50% amino acid identity with GLP-1, activates the GLP-1 receptor and likewise has been shown to reduce hyperglycemia in diabetic patients.
Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid gastrointestinal regulatory peptide that, like GLP-1, stimulates insulin secretion from pancreatic β (beta) cells in the presence of elevated blood glucose levels. It is derived by proteolytic processing from a 133-amino acid precursor, preproGIP.
Interestingly, novel glucagon-GLP-1 dual acting receptor agonists are currently in pre-clinical development (see, e.g., WO2011/006497). In comparison to GLP-1 analogues, glucagon-GLP-1 dual agonists are associated with more profound and sustained body weight loss in animal models on top of the improvements in glycemic control. Thus, glucagon based drugs may have promise for the treatment of type 2 diabetes mellitus and/or obesity.
Incretins are gastrointestinal hormones that regulate blood glucose by enhancing glucose-stimulated insulin secretion (Drucker, D J and Nauck, M A, Lancet 368: 1696-705 (2006)). Two of the above mentioned peptides are known as incretins: GLP-1 and GIP. The discovery of the incretins has led to the development of two new classes of drugs for the treatment of diabetes mellitus. Thus, injectable GLP-1 receptor agonists, and small molecule compounds (oral DPP-4 inhibitors) that inhibit enzymatic inactivation of both endogenous GLP-1 and GIP, are now on the market (GLP-1 receptor agonists: Byetta™, Bydureon™, Lixisenatide™ and Liraglutide™, and DPP-4 inhibitors: Januvia™, Galvus™, Onglyza™ and Trajenta™). Apart from the acute effects of GLP-1 and GIP on insulin secretion, the two peptides also have long term effects. Evidence from several labs indicates that GLP-1 R agonists protect pancreatic β-cells by inhibiting apoptosis and enhancing proliferation. For instance, the study by Farilla et al. showed that GLP-1 had anti-apoptotic effects in human islets (Farilla, L, Endocrinology 144: 5149-58 (2003)). Such effects have not been reported for GIP until recently. In 2010, Weidenmaier et al. reported that a DPP-4 resistant GIP analogue has anti-apoptotic effects (Weidenmaier, S D, PLOS One 5(3): e9590 (2010)). Interestingly, in a mice model of diabetes and obesity the combination of the GLP-1 receptor agonist Liraglutide and an acylated GIP analogue show superior effects compared to treatment with Liraglutide or GIP analogue alone (Gault, V A, Clinical Science 121: 107-117 (2011)).
Chronic treatment with the GLP-1 receptor agonists causes significant weight loss in diabetic humans. Interestingly, extended use of DPP-4 inhibitors in similar patients does not consistently change body weight. Evidence suggests (Matthias Tschöp oral presentation at ADA (American Diabetes Association), 2011) that body weight loss associated with GLP-1 agonist treatment is enhanced when GLP-1 and GIP are co-administered. In rodents, co-administration of GLP-1 and GIP results in greater body weight loss than GLP-1 treatment alone (Finan, Sci Transl Med. 2013; 5(209):209ra151. Irwin N et al, 2009, Regul Pept; 153: 70-76. Gault et al, 2011, Clin Sci; 121:107-117). Thus, in addition to improving blood glucose, GIP may also enhance GLP-1-mediated body weight loss. In the same presentation it was also shown that combining glucagon, GLP-1 and GIP receptor agonism led to further body weight loss in DIO mice.
By combining glucagon, GLP-1 and GIP receptor agonism in novel inventive peptides it is anticipated that superior glycemic control and body weight loss can be achieved. Such peptides are likely to have strong incretin actions and improved β-cell preservation from the GLP-1 and GIP components, and have improved body weight loss from all three components by stimulating energy expenditure, lipolysis and reducing food intake.